Process for the preparation of 3-haloalkylpyrazoles

ABSTRACT

A process for the preparation of a compound of formula IX: 
     
       
         
         
             
             
         
       
     
     wherein R 1  is difluoromethyl, and
         R 3  is methyl or ethyl.

This application is a divisional of U.S. application Ser. No.15/145,232, filed on May 3, 2016, which is a divisional of U.S. patentapplication Ser. No. 13/816161 having a § 371 date of Jul. 1, 2013,which is a 371 of International Application No. PCT/EP2011/063360 filedAug. 3, 2011, which claims priority to U.S. Provisional Application No.61/372,122 filed Aug. 10, 2010 the contents of all of which areincorporated herein by reference.

The present invention relates to N-alkylation of substituted pyrazoles.In particular, the invention relates to the isomerisation of N-alkylatedsubstituted pyrazoles and to the preparation of selected isomers ofN-alkylated substituted pyrazoles.

Fungicides for use in crop protection are produced on a very largescale, e.g. thousands of tons per year. Given the scale on whichfungicides are produced, any improvement in the production process canrepresent significant cost savings.

N-alkylated substituted pyrazoles, for example ethyl3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (DFPE), arevaluable intermediates in the preparation of a number of fungicides,including Sedaxane, Isopyrazam and others. In DFPE only one of thenitrogen atoms in the pyrazole ring is alkylated.

According to WO 2006/045504, regioselective N-alkylation of substitutedpyrazoles may be achieved by reacting the corresponding substitutedpyrazoles with trialkyl phosphates or trialkylphosphonates. However, itwould be desirable to increase the yield of the non-iso isomer in orderto reduce costs and wastage in commercial production.

In a first aspect, the invention provides a process for the preparationof a compound of formula I:

wherein R¹ is C₁-C₄haloalkyl;

R² is optionally substituted alkyl, optionally substituted aryl oroptionally substituted heteroaryl; and

R³ is methyl or ethyl;

comprising reacting a compound of formula IV:

wherein R¹, R² and R³ are as defined for the compound of formula I;

with an alkylating agent in the presence of an amide.

The compound of formula IV is referred to herein as the “iso” isomerwith respect to compounds of formula I.

The alkyl groups appearing in the above substituent definitions may bestraight-chain or branched and are, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl,preferably methyl or ethyl. Halogen is generally fluorine, chlorine,bromine or iodine, preferably fluorine. C₁-C₄ haloalkyl groups arederived from the mentioned C₁-C₄alkyl groups and are preferablydifluoromethyl or trifluoromethyl.

Aryl refers to aromatic hydrocarbon ring systems which may be a singlering or multiple rings which are fused together or linked covalently.Examples for aryl groups are phenyl, naphthyl, tetrahydronaphthyl,indanyl, indenyl, anthracenyl, phenanthrenyl and biphenyl.

Heteroaryl refers to aromatic ring systems comprising mono-, bi- ortricyclic systems wherein at least one oxygen, nitrogen or sulfur atomis present as a ring member. Examples are furyl, thienyl, pyrrolyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, benzothiophenyl,benzofuranyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl,benzoxazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl,quinazolinyl, cinnolinyl and naphthyridinyl.

R² for example may be optionally substituted alkyl, optionallysubstituted aryl or optionally substituted heteroaryl. This means thatthe alkyl, aryl and heteroaryl groups may or may not carry one or moreidentical or different substituents. Normally not more than threesubstituents are present at the same time. Examples of substituents are:halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl,haloalkenyl, cycloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy,cycloalkoxy, alkenyloxy, haloalkenyloxy, alkynyloxy, haloalkenyloxy,alkylthio, haloalkylthio, cycloalkylthio, alkenylthio, alkynylthio,alkylcarbonyl, haloalkylcarbonyl, cycloalkylcarbonyl, alkenylcarbonyl,alkynylcarbonyl, alkoxyalkyl, cyano, nitro, hydroxy, mercapto, amino,alkylamino and dialkylamino.

Preferred optional substituents are C₁-C₈ alkyl, halo-C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₃-C₈cycloalkyl-C₁-C₈alkyl, C₂-C₈ alkenyl, halo-C₂-C₈alkenyl, C₃-C₈ cyclo-C₂-C₈ alkenyl, C₂-C₈ alkynyl, halo-C₂-C₈ alkynyl,C₁-C₈ alkoxy, halo-C₁-C₈ alkoxy, C₃-C₈ cycloalkoxy, C₂-C₈ alkenyloxy,halo-C₂-C₈ alkenyloxy, C₂-C₈ alkynyloxy, halo-C₂-C₈ alkenyloxy, C₁-C₈alkylthio, halo-C₁-C₈ alkylthio, C₃-C₈ cycloalkylthio, C₂-C₈ alkenylthio, C₂-C₈ alkynylthio, C₁-C₈ alkylcarbonyl, halo-C₁-C₈alkylcarbonyl, C₃-C₈ cycloalkylcarbonyl, C₂-C₈ alkenylcarbonyl, C₂-C₈alkynylcarbonyl, C₁-C₈alkoxy-C₁-C₈alkyl, cyano, nitro, hydroxy,mercapto, amino, C₁-C₈ alkylamino and C₁-C₈dialkylamino.

More preferred optional substituents are C₁-C₄ alkyl, halo-C₁-C₄ alkyl,C₃-C₆ cycloalkyl, C₃-C₆cycloalkyl-C₁-C₄alkyl, C₂-C₄ alkenyl, halo-C₂-C₄alkenyl, C₃-C₆ cyclo-C₂-C₄ alkenyl, C₂-C₄ alkynyl, halo-C₂-C₄ alkynyl,C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₃ ^(-C) ₆ cycloalkoxy, C₂-C₄alkenyloxy, halo-C₂-C₄ alkenyloxy, C₂-C₄ alkynyloxy, halo-C₂-C₄alkenyloxy, C₁-C₄ alkylthio, halo-C₁-C₄ alkylthio, C₃-C₆ cycloalkylthio,C₂-C₄ alkenylthio, C₂-C₄ alkynylthio, C₁-C₄ alkylcarbonyl, halo-C₁-C₄alkylcarbonyl, C₃-C₆ cycloalkylcarbonyl, C₂-C₄ alkenylcarbonyl, C₂-C₄alkynylcarbonyl, C₁-C₄ alkoxy-C₁-C₄ alkyl, cyano, nitro, hydroxy,mercapto, amino, C₁-C₄alkylamino and C₁-C₄dialkylamino.

More preferred optionally substituents are C₁-C₄ alkyl, C₁-C₄ haloalkyl,C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, halogen, hydroxy, cyano, nitro andamino.

Typical examples for optionally substituted aryl include 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 2-cyanophenyl, 3-cyanophenyl,4-cyanophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl,3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2,3-difluorophenyl,2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl,2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3-dibromophenyl,2,4-dibromophenyl, 2,5-dibromophenyl, 2,6-dibromophenyl,3,4-dibromophenyl, 3,5-dibromophenyl, 2,3-dimethylphenyl,2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl,3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dimethoxyphenyl,2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl,3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,3-dicyanophenyl,2,4-dicyanophenyl, 2,5-dicyanophenyl, 2,6-dicyanophenyl,3,4-dicyanophenyl, 3,5-dicyanophenyl, 2,3-bis(trifluoromethyl)phenyl,2,4-bis(trifluoromethyl)phenyl, 2,5-bis(trifluoromethyl)phenyl,2,6-bis(trifluoromethyl)phenyl, 3,4-bis(trifluoromethyl)phenyl,3,5-bis(trifluoromethyl)phenyl, 2,3-bis(trifluoromethoxy)phenyl,2,4-bis(trifluoromethoxy)phenyl, 2,5-bis(trifluoromethoxy)phenyl,2,6-bis(trifluoromethoxy)phenyl, 3,4-bis(trifluoromethoxy)phenyl,3,5-bis(trifluoromethoxy)phenyl, 2-chloro-5-fluorophenyl,2-fluoro-5-methylphenyl, 2-fluoro-5-methoxyphenyl,5-chloro-2-fluorophenyl, 2-chloro-5-methylphenyl,2-chloro-5-methoxyphenyl, 5-fluoro-2-methylphenyl,5-chloro-2-methylphenyl, 5-methoxy-2-methylphenyl,5-fluoro-2-methoxyphenyl, 5-chloro-2-methoxyphenyl and2-methoxy-5-methylphenyl.

Typical examples for optionally substituted heteroaryl include5-methyl-3-trifluoromethylpyrazol-1-yl,3-methyl-5-trifluoromethylpyrazol-1-yl,3,5-bis-trifluoromethylpyrazol-1-yl, 3,5-dimethylpyrazol-1-yl,5-ethyl-3-trifluoromethylpyrazol-1-yl,5-methyl-3-trifluoromethoxypyrazol-1-yl,2-methyl-4-trifluoromethylimidazol-1-yl,4-methyl-2-trifluoromethylimidazol-1-yl,2,4-bis-trifluoromethylimidazol-1-yl, 2,4-dimethylimidazol-1-yl,2-ethyl-4-trifluoromethylimidazol-1-yl,2-methyl-4-trifluoromethoxyimidazol-1-yl,5-methyl-3-trifluoromethyl[1,2,4]triazol-1-yl,3-methyl-5-trifluoromethyl[1,2,4]triazol-1-yl,3,5-bis-trifluoromethyl[1,2,4]triazol-1-yl and3,5-dimethyl[1,2,4]triazol-1-yl,5-ethyl-3-trifluoromethyl[1,2,4]triazol-1-yl,5-methyl-3-trifluoromethoxy[1,2,4]triazol-1-yl.

Cycloalkyl on its own or as part of another substituent is, dependingupon the number of carbon atoms mentioned, for example, cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl.

Alkoxy on its own or as part of another substituent is, depending uponthe number of carbon atoms mentioned, for example methoxy, ethoxy,1-propoxy, 2-propoxy, n-butoxy, 2-n-butoxy, or 2-tert-butoxy.

Alkenyl on its own or as part of another substituent is, depending uponthe number of carbon atoms mentioned, for example, ethenyl, allyl,propen-1-yl, buten-2-yl, buten-3-yl, penten-1-yl, penten-3-yl,hexen-1-yl or 4-methyl-penten-3-yl.

Alkynyl on its own or as part of another substituent is, depending uponthe number of carbon atoms mentioned, for example, ethynyl, propyn-1-yl,propyn-2-yl, butyn-1-yl, butyn-2-yl, 1-methyl-2-butynyl, hexyn-1-yl or1-ethyl-2-butynyl.

Preferably, R¹ is difluoromethyl or trifluoromethyl;

Preferably R² is C₁-C₈ alkyl, phenyl, or phenyl-C₁-C₈ alkyl, wherein thealkyl, phenyl and phenylalkyl are each optionally substituted with oneor more of, e.g. 1 to 3, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy,halo-C₁-C₄ alkoxy, halogen, hydroxy, cyano, nitro and amino. Morepreferably R² is C₁-C₈ alkyl or C₁-C₈ haloalkyl, phenyl or benzyl,wherein the phenyl and benzyl are each optionally substituted withhalogen, e.g. 1 to 3 halogen atoms. Even more preferably R² is C₁-C₆alkyl, e.g. C₁-C₄ alkyl. Most preferably R² is methyl or ethyl.

Preferably R³ is methyl.

The processes according to the invention are suitable preferably for thepreparation of compounds of formula I wherein R¹ is difluoromethyl ortrifluoromethyl; R² is C₁-C₆ alkyl, e.g. ethyl; and R³ is methyl.

The processes according to the invention are especially suitable for thepreparation of compounds of formula I wherein R¹ is difluoromethyl.

The processes according to the invention are very especially suitablefor the preparation of compounds of formula I wherein R¹ isdifluoromethyl, R² is ethyl, and R³ is methyl.

The processes according to the invention are also very especiallysuitable for the preparation of compounds of formula I wherein R¹ istrifluoromethyl; R² is ethyl, and R³ is methyl.

The compound of formula IV may provided as a mixture comprising thecompound of formula IV and the compound of formula I. For example,compounds of formula IV may be produced by N-alkylating thecorresponding pyrazole. This will generally result in a mixture ofcompounds of formula IV and formula I. The present invention provides aprocess for increasing the proportion of the compound of formula I in amixture comprising a compound of formula I and a compound of formula IV.

The compound of formula IV may be provided as a mixture comprising acompound of formula I and a compound of formula IV, and wherein saidmixture is prepared by N-alkylating a compound of formula II:

wherein R¹ and R² are as defined for the compound of formula I; e.g.thereby producing a mixture comprising a compound of formula I and acompound of formula IV.

It may be advantageous in some cases to N alkylate the correspondingsubstituted pyrazole and isomerise any compound of formula IV producedfrom the alkylation substantially at the same time, e.g. simultaneously.The reaction may be performed in one step.

Accordingly, in a further aspect, the invention provides a process, e.g.a regioselective process, for the preparation of a compound of formulaI:

wherein R¹ is C₁-C₄haloalkyl;

R² is optionally substituted alkyl, optionally substituted aryl oroptionally substituted heteroaryl;

R³ is methyl or ethyl;

comprising reacting a compound of formula II:

wherein R¹ and R² are as defined for the compound of formula I;

with an alkylating agent in the presence of an amide.

Preferred definitions of R¹, R² and R³ are the same as those givenabove. Most preferably R¹ is difluoromethyl, R² is C₁-C₆ alkyl e.g.ethyl and R³ is methyl.

Without being bound by theory, it is thought that the alkylating agentand the amide act as a catalyst to inter-convert the compound of formulaI and the compound of formula IV, thereby promoting the proportions ofthe compounds of formula I and IV to thermodynamic equilibrium.

In a further aspect, the invention provides a process forinter-converting a compound of formula IV and a compound of formula Iaccording to Scheme I:

wherein R¹ is C₁-C₄haloalkyl;

R² is optionally substituted alkyl, optionally substituted aryl oroptionally substituted heteroaryl; and

R³ is methyl or ethyl;

using an alkylating agent and an amide as inter-conversion reagents.

Preferred definitions of R¹, R² and R³ are the same as those givenabove. Most preferably R¹ is difluoromethyl, R² is C₁-C₆ alkyl, e.g.ethyl, and R³ is methyl.

Preferably the amide is a tertiary amide, e.g. a compound of formula XX:

wherein R⁴ is H or C₁-C₄ alkyl;

R⁵ is C₁-C₄ alkyl;

R⁶ is C₁-C₄ alkyl;

or R⁴ and R⁵ are together C₂-C₅ alkyene;

or R⁵ and R⁶ are together C₂-C₅ alkyene.

More preferably R⁴ is H or C₁-C₄ alkyl; R⁵ is C₁-C₄ alkyl; or R⁴ and R⁵are together C₂-C₅ alkyene; and R⁶ is C₁-C₄ alkyl. Most preferably theamide is N,N-dimethylformamide, N,N-dimethylacetamide orN-methyl-2-pyrollidone.

Without being bound by theory it is understood that inter-conversion ofthe compound of formula I and IV proceeds via the pyrazolium cation. Thealkylating agent is preferably a strong alkylating agent, e.g. one thatis capable of alkylating a compound of formula IV to form thecorresponding pyrazolium cation, e.g. a compound of formula IVa

wherein R¹, R² and R³ are as defined for a compound of formula IV.

The alkylating agent and amide are present simultaneously in thereactions of the invention, e.g. as a mixture comprising the alkylatingagent and amide. They may be added separately or simultaneously. Whenadded simultaneously, if desired, they may be added as a salt, e.g.formed by alkylation of the amide by the alkylating agent. Similarly,the amide and alkylating agent may form ions in situ arising fromalkylation of the amide by the alkylating agent, thereby creating an“ionic liquid”. In other words, the reactions of the invention maycomprise a non-aqueous phase containing dispersed ions arising fromalkylation of the amide by the alkylating agent.

The alkylating agent may be one that is capable of alkylating an amide,preferably a tertiary amide, e.g. to form a compound of formula XXa

wherein R⁴, R⁵ and R⁶ are as defined for a compound of formula XX and R³is methyl or ethyl.

More preferably the alkylating agent is a compound of formula III:

wherein R³ is methyl or ethyl.

Preferably the reactions of the invention employ a methylating agent orethylating agent, more preferably a methylating agent, e.g. amethylating agent this is capable of methylating a compound of formulaIV and/or an amide such as a tertiary amide, e.g. a compound of formulaXX. More preferably the methylating agent is a compound of formula IIIin which R³ is methyl, e.g. dimethylsulphate.

In one embodiment the alkylating agent is dimethylsulphate and the amideis N,N-dimethylformamide. In another embodiment the alkylating agent isdimethylsulphate and the amide is N,N-dimethylacetamide. In anotherembodiment the alkylating agent is dimethylsulphate and the amide isN-methyl-2-pyrollidone.

The reaction according to the invention can be carried out in an inertsolvent, preferably an anhydrous inert solvent. Suitable solvents are,for example, xylene, mesitylene, tert-butyl benzene, chlorobenzene,1,2-dichlorobenzene, Decalin, dibutyl ether, dipentyl ether, diphenylether and anisole. The reaction according to the invention is preferablycarried out neat, e.g. without an additional solvent.

The temperature of the reaction in which the compound of formula IV isconverted into the compound of formula I may be carried out at atemperature of e.g. 50 to 250° C., e.g. 100 to 200° C., e.g. 140 to 180°C. Preferably the reaction is performed at at least 100° C., at least120° C., at least 140° C., at least 160° C. A person skilled in the artwould be able to optimise the reaction to find the most suitabletemperature.

The alkylating agent may be present in the reaction at 0.05 molarequivalents to 5 molar equivalents. We have found that increasing theconcentration of alkylating agent increases the rate at whichinter-conversion takes place, however larger amount of alkylating agentcan affect yield. The amount of alkylating agent is preferably less than1 molar equivalent. Preferably the alkylating agent is 0.2 molarequivalents to 0.7 molar equivalents, most preferably 0.3 molarequivalents to 0.5 molar equivalents. Equivalents are relative to themolar amount of the compound of formula IV or the compound of formula IVand compound of formula I when both are present.

The amide may be present in the reaction at 0.1 molar equivalents to 10molar equivalents, preferably 0.2 molar equivalents to 2 molarequivalents, most preferably 0.5 molar equivalents to 1.5 molarequivalents. Equivalents are relative to the molar amount of thecompound of formula IV or the compound of formula IV and the compound offormula I when both are present. In one embodiment the alkylating agentand amide are present in a catalytic amount.

WO 2008/145257 describes synthesis routes to N-alkylated substitutedpyrazoles using methylhydrazine. The use of methylhydrazine instead ofhydrazine allows synthesis of N-alkylated substituted pyrazoles in whicha methyl group is placed on the desired pyrazole nitrogen atom therebyavoiding the need for a separate step for alkylation. The presentinvention now provides an alkylation step that allows synthesis of thenon-iso isomers with high regioselectivity. This makes a route involvinghydrazine more feasible.

In a further aspect, the invention provides a process, e.g. aregioselective process, for the preparation of a compound of formula I:

wherein R¹ is C₁-C₄haloalkyl;

R² is optionally substituted alkyl, optionally substituted aryl oroptionally substituted heteroaryl; and

R³ is methyl or ethyl;

comprising

a. reacting a compound of formula V:

wherein R¹ is C₁-C₄haloalkyl;

R² is optionally substituted alkyl, optionally substituted aryl oroptionally substituted heteroaryl; and

R⁷ is hydrogen, optionally substituted alkyl, optionally substitutedaryl or optionally substituted heteroaryl;

with hydrazine to produce a compound of formula II:

wherein R¹ and R² are as defined for formula I; and

b. reacting the compound of formula II with an alkylating agent in thepresence of an amide.

Preferred definitions of R¹, R² and R³ are the same as those given aboveand R⁷ is preferably hydrogen or C₁-C₆ alkyl. Most preferably R¹ isdifluoromethyl, R² is C₁-C₆ alkyl e.g. ethyl, R³ is methyl and R⁷ ishydrogen or C₁-C₆ alkyl e.g. ethyl. Preferably the alkylating agent andamide are as described above.

In a further aspect alkylation of a compound of formula II andisomerisation may be carried out in separate steps. Accordingly, in afurther aspect the invention provides a process, e.g. a regioselectiveprocess, for the preparation of a compound of formula I:

wherein R¹ is C₁-C₄haloalkyl;

R² is optionally substituted alkyl, optionally substituted aryl oroptionally substituted heteroaryl; and

R³ is methyl or ethyl;

comprising

b1. reacting a compound of formula II:

wherein R¹ and R² are as defined for the compound of formula I; with analkylating agent to produce a mixture comprising a compound of formula Iand a compound of formula IV

wherein R¹, R² and R³ are as defined for the compound of formula I; and

b2. reacting the mixture from b1. with an alkylating agent in thepresence of an amide.

Preferred definitions of R¹, R² and R³ are the same as those givenabove. Most preferably R¹ is difluoromethyl, R² is C₁-C₆ alkyl e.g.ethyl and R³ is methyl.

The alkylating agent used in step b1. may or may not be the same as thealkylating agent used in step b2. Preferred alkylating agents for use instep b2 are described above. The alkylating agent used in step b1. maybe selected from known alkylating agents. Suitable alkylating agentsinclude for example alkyl phosphates, alkyl phosphonates, alkylphosphites, alkyl sulphates and alkyl carbonates, for example a compoundof formula III, XXI, XXII or XXIII:

wherein

R³ is methyl or ethyl;

R⁸ is hydrogen, optionally substituted alkyl, optionally substitutedaryl or optionally substituted heteroaryl, preferably hydrogen or C₁-C₆alkyl, e.g. ethyl; and

n is 0 or 1, preferably 1.

Preferred alkylating reagents are compounds of formula III and XXI,particularly alkylphosphates and alkylsulphonates. Dimethylsulphate andtrimethylphosphate are particularly preferred. In one embodiment thealkylating reagent is dimethylsulphate, in another embodiment thealkylating reagent is trimethylphosphate. Alkylation may be performed inthe presence of a base. Suitable bases are for example hydroxides andcarbonates, e.g. of alkali metals. Methods of alkylating compounds offormula II are described for example in WO 2006/045504.

The compounds of formula II are known or can be prepared using hydrazineanalogously to processes known in the literature. For example, suchcompounds can be prepared from the 3-oxo-carboxylic acid esters on whichthey are based by means of a two-step synthesis by reaction withtrimethyl orthoformate and subsequent reaction with hydrazine. Suchreactions are described, for example, in JP-2000-044541. A furthersynthesis route for the preparation of compounds of formula II isdescribed in JP-2001-322983, wherein, for example, 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester is prepared starting from3-chloro-4,4,4-trifluoro-2-formyl-2-butenoic acid ethyl ester byreaction with hydrazine. Also, WO 2006/045504 discusses procedures thatmay be employed for producing compounds of formula II from compounds offormula V using hydrazine. Compounds of formula III and XX arecommercially available.

In a further aspect of the invention, there is provided use of analkylating agent and an amide, e.g. as catalyst, in the conversion of acompound of formula IV:

wherein R¹ is C₁-C₄haloalkyl,

R² is optionally substituted alkyl, optionally substituted aryl oroptionally substituted heteroaryl; and

R³ is methyl or ethyl;

into a compound of formula I:

wherein R¹, R² and R³ are as defined for the compound of formula IV.

Preferred definitions of R¹, R², and R³ are the same as those givenabove. Most preferably R¹ is difluoromethyl, R² is C₁-C₆ alkyl e.g.ethyl and R³ is methyl. Preferably the alkylating agent and amide are asdescribed above.

In a further aspect there is provided a catalyst, e.g. for converting acompound of formula IV to a compound of formula I, comprising analkylating agent and an amide. Preferably the alkylating agent and amideare as described above. Such a catalyst will usually exist as an ionicliquid.

In a further aspect of the invention there is provided a process, e.g. aregioselective process, for preparing a compound of formula VI:

comprising reacting a compound of formula VII:

with a compound of formula VIII:

in the presence of an amide selected from dimethylformamide,N,N-dimethylacetamide and N-methyl-2-pyrollidone.

Compounds of formula I may be subsequently converted into thecorresponding acid. Such compounds may also be useful intermediates inthe production of fungicides, see e.g. WO 2008/145257. For example,compounds of formula I may be converted into compounds of formula IX:

wherein R¹ and R³ are as defined for the compound of formula I; byhydrolysing the compound of formula I.

Accordingly, the invention provides a process for the preparation of acompound of formula IX:

wherein R¹ is C₁-C₄haloalkyl; and

R³ is methyl or ethyl;

comprising

1. preparing a compound of formula I:

wherein R¹ and R³ are as defined for the compound of formula IX; and

R² is optionally substituted alkyl, optionally substituted aryl oroptionally substituted heteroaryl;

according to the invention; and

2. hydrolysing the compound of formula I to produce the compound offormula IX.

Preferred definitions of R¹, R², and R³ are the same as those givenabove. Most preferably R¹ is difluoromethyl, R² is C₁-C₆ alkyl e.g.ethyl and R³ is methyl.

Hydrolysis of the compound of formula I may be achieved by performingthe steps:

i) saponifying that compound in situ leading to the formation of acompound of formula I by

ii) adding a base to form the anion of the compound of formula IX;

ii′) adding an acid to form the compound of formula IX;

e.g. as described in WO 2008/145257.

In a further aspect the invention provides a process for the preparationof a compound of formula X:

wherein R¹ is C₁-C₄haloalkyl;

R³ is methyl or ethyl;

A is thienyl, phenyl, or ethylene each optionally substituted by one tothree groups independently selected from halogen, methyl and methoxy;

B is a direct bond, cyclopropylene, an annelated bicyclo[2.2.1]heptane-or bicyclo[2.2.1]heptene ring;

D is hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, C₃-C₆ cycloalkyl, C₁-C₆ alkylidene, C₁-C₆haloalkylidene, phenyl or phenyl optionally substituted by one to threesubstituents independently selected from halogen and trihalomethylthio;comprising providing a compound of formula IX:

wherein R¹ is C₁-C₄haloalkyl and R³ is methyl or ethyl;

according to the processes described above; and

reacting the compound of formula IX or the corresponding acid-halidewith a compound of formula XI:

H₂N-A-B-D   (XI)

wherein A, B and D are as defined for the compound of formula X.

The compound of formula X is preferably a compound of formula XII(Isopyrazam), a compound of formula XIII (Sedaxane), a compound offormula XIV, a compound of formula XV (Penthiopyrad), a compound offormula XVI (Bixafen), a compound of formula XVII (Fluxapyroxad), acompound of formula XVIII, or a compound of formula XIX:

The step of reacting the compound of formula IX or the correspondingacid-halide with a compound of formula XI may be performed according toknown methods, e.g. as described in WO 2004/035589 or WO 2009/135860.For example, the compound of formula IX may be treated with ahalogenating agent, such as thionyl chloride, oxalyl chloride, phosgene,SF₄, DAST, deoxofluor or thionylbromide to provide the acid-halogen,e.g. the acid chloride, which may then be reacted with the compound offormula XI in the presence of a suitable base, e.g. LiOH, KOH, NaOH,NEt₃, NaHCO₃, KHCO₃, Na₂CO₃ or K₂CO₃, e.g. in a solvent such as toluene,xylenes, dichloromethane, ethyl acetate or DMF, e.g. at −10° C. to 30°C.

Isopyrazam, Sedaxane, Penthiopyrad, Fluxapyroxad and Bixafen are knownfungicides. The compound of formula XIV is known, e.g. from WO2007/048556, the compound of formula XVIII is known e.g. from WO2010/000612, the compound of formula XIX is known e.g. from WO2008/053044.

We have found that the compounds of formula I and IV have differentboiling points which may be exploited to separate the compound offormula I from the compound of formula IV. Thus, the process maycomprise separating a mixture of compounds of formula I and IV bydistillation. For example, iso-DFPE has a boiling point of approximately95° C/10 mbar, whereas DFPE has a boiling point of approximately 120°C/1 mbar. This separation step may be performed after completion ofisomerisation or may be performed simultaneously with isomerisation,e.g. when the process is continuous. The compound of formula I may bepurified by crystallisation.

Table 1 shows examples of compounds of formula I of the invention.

TABLE 1 Compounds of formula I (I)

Comp. No. R₁ R₂ R₃ A1 CF₂H CH₂CH₃ CH₃ A2 CF₂H CH₃ CH₃ A3 CF₂H CH₃ CH₂CH₃A4 CF₂H CH₂CH₃ CH₂CH₃ A5 CF₃ CH₂CH₃ CH₃ A6 CF₃ CH₃ CH₃ A7 CF₃ CH₃ CH₂CH₃A8 CF₃ CH₂CH₃ CH₂CH₃

The present invention will now be described by way of the followingnon-limiting Examples. Those skilled in the art will promptly recognizeappropriate variations from the procedures both as to reactants and asto reaction conditions and techniques.

All references mentioned herein are incorporated by reference in theirentirety. All aspects and preferred features of the invention may becombined with each other, except where this is evidently not possible.

FIGURES

FIG. 1

FIG. 1 shows that ethyl5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (iso-DFPE) revertsinto ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (DFPE)under conditions according to the invention. The Y axis indicates theamount of DFPE as a proportion of the combined amount of DFPE andiso-DFPE. The X axis indicates time. Experimental details are describedunder Example 8. DMF is dimethylformamide, NMP isN-methyl-2-pyrollidone, DMA is N,N-dimethylacetamide, DMS isdimethylsulphate. “DMF/DMS 0.5 equiv” means pre-formed DMF/DMS salt asdescribed in Example 1, i.e., by treatment of 0.5 molar equivalents ofDMF and 0.5 molar equivalents of DMS relative to the combined amount ofDFPE and iso-DFPE.

FIG. 2

FIG. 2 shows that ethyl5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (iso DFPE) revertsinto ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (DFPE)under conditions according to the invention. The Y axis indicates theamount of DFPE as a proportion of the combined amount of DFPE andiso-DFPE. The X axis indicates time. Experimental details are describedunder Example 9.

EXAMPLES Example 1

Preparation of an amide/dimethylsulfate salt: dimethylsulfate (1 molarequivalent) and amide (1.2 molar equivalents), are heated to 70° C. for1.5 hours. Once cooled, the resulting solution is available for use.

Example 2

A solution of ethyl5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (iso-DFPE) (˜98%,56.1 g, 0.27 mol) and dimethylformamide (27.1 g, 0.37 mol) was stirredat room temperature. Dimethylsulphate (12.1 g, 0.10 mol) was added. Theresulting solution was heated gradually to 160° C. and held for 4 hours.The solution was then heated gradually to 170° C. over 30 minutes andheld for additional 1.5 hours for a total reaction time of 6 hours at160° C. Quantitative GC analysis of the reaction mass indicated thesolution yields to be 49.8 g of ethyl3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (DFPE) and 5.4 gof iso-DFPE.

Example 3

A solution of ethyl5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (iso-DFPE) (>99%,2.04 g, 0.01 mol), N,N-dimethylformamide /dimethylsulfate salt (1.00 g,0.005 mol) and N,N-dimethylformamide (0.37 g, 0.005 mol) was stirred atroom temperature. The resulting solution was heated gradually to 160° C.and held for 7 hours. The conversion to ethyl3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (DFPE) wasapproximately 95.7%.

Example 4

A solution of ethyl5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (iso-DFPE) (>99%,2.04 g, 0.01 mol), N-methyl-2-pyrrolidone/dimethylsulfate salt (1.12 g,0.005 mol) and N-methyl-2-pyrrolidone (0.50 g, 0.005 mol) was stirred atroom temperature. The resulting solution was heated gradually to 160° C.and held for 7 hours. The conversion to ethyl3-(difluoromethyl)-1-methyl-1 H-pyrazole-4-carboxylate (DFPE) wasapproximately 93.5%.

Example 5

A solution of ethyl5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (iso-DFPE) (>99%,2.04 g, 0.01 mol), N,N-dimethylacetamide/dimethylsulfate salt (1.06 g,0.005 mol) and N,N-dimethylacetamide (0.44 mg, 0.005 mol) was stirred atroom temperature. The resulting solution was heated gradually to 160° C.and held for 7 hours. The conversion to ethyl3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (DFPE) wasapproximately 82.2%.

Example 6

To 147.2 g of a crude mixture of ethyl5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (iso-DFPE) andethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (DFPE)(iso-DPFE: 50.1 g; DFPE: 85.3 g) was added 43.8 g ofN,N-dimethylformamide and 12.6 g of dimethylsulfate. The resultingsolution was heated gradually to 160° C. and held for 4 hours. Thesolution was then heated gradually to 170° C. over 30 minutes and heldfor an additional 1.5 hours for a total reaction time of 6 hours at≥160° C. Quantitative GC analysis of the reaction mass indicated thesolution yields to be 120.1 g of DFPE and 9.1 g of iso-DFPE. Theunreacted iso-DFPE was then distilled out and recycled in the nextbatch. The crude product of DFPE from distillation bottom was dissolvedin toluene and can be used directly for the next step, e.g. hydrolysis,without any further purification.

Example 7

To 1.9 g of ethyl 3-difluoromethylpyrazole-4-carboxylate (NHDFPE) wasadded 2.5 g of N,N-dimethylformamide/dimethylsulfate salt. The mixturewas heated to 160° C. and stirred for 7 hours. The isomer ratio of ethyl3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (DFPE): ethyl5-(difluoromethyl)-1-methyl-1 H-pyrazole-4-carboxylate (iso-DFPE) at endof reaction time based on GC analysis was 98:2.

Example 8

In each reactor of a multi-pot reaction block was placed 2.0 g (10 mmol)of ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate(iso-DPFE) and amide/dimethylsulfate salt. The reaction block was heatedto 170° C. and stirred for 8 hours. Samples were taken periodically forGC analysis. Results are shown in FIG. 1.

Example 9

In each reactor of a multi-pot reaction block was placed 2.0 g (10 mmol)of ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate(iso-DPFE), DMF/dimethylsulfate salt (1.0-2.5 mmol), and 0.7 g DMF (10mmol). The reaction block was heated to 150° C. and stirred for 8 hours.Samples were taken periodically for GC analysis. Results are shown inFIG. 2.

What is claimed is:
 1. A process for the preparation of a compound offormula IX:

wherein R¹ is difluoromethyl, and R³ is methyl or ethyl; comprising a)preparing a compound of formula I:

wherein R¹ and R³ are as defined for the compound of formula IX; and R²is optionally substituted alkyl, optionally substituted aryl oroptionally substituted heteroaryl; and b) hydrolysing the compound offormula I to produce the compound of formula IX.
 2. A process accordingto claim 1, wherein R² is C₁-C₆ alkyl; and R³ is methyl.